Gut microbiota-derived metabolites and EVs-mediated signaling in type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by systemic insulin resistance, chronic low-grade inflammation, and progressive metabolic dysfunction. Increasing evidence identifies the gut microbiota as a central regulator of host immunometabolism through a diet-microbiota-host axis. Gut microbiota-derived metabolites, including short-chain fatty acids, bile acids, branched-chain amino acids, and trimethylamine N-oxide, integrate endocrine signaling, intracellular metabolic pathways, and inflammatory responses across intestinal and systemic compartments, thereby shaping glucose homeostasis and metabolic balance. Diet acts as an upstream determinant by modulating microbial composition and metabolic activity. Beyond soluble metabolites, extracellular vesicles have emerged as an additional mode of intercellular communication. Vesicles derived from diet or microbiota carry bioactive cargos such as proteins, lipids, and small RNAs, enabling the transfer of functional signals that may influence both microbial ecology and host immunometabolic processes. This review summarizes metabolite-dependent and vesicle-mediated signaling pathways and highlights how these interconnected mechanisms position the gut microbiota as a signaling hub linking dietary inputs to host cellular regulation. This framework provides a conceptual basis for microbiota-targeted strategies in the prevention and treatment of type 2 diabetes.